The paper of the month is a systematic review (SR) and meta-analysis compiling data from both observational and intervention studies on the association between chronic low-grade inflammation and working conditions. The paper reflects an increasing interest within the environmental and occupational field for inflammatory markers possible preceding chronic disease with potentially important windows of opportunity for prevention of chronic disease.
The most interesting part of the SR is the work place intervention studies (16, including 8 RCT), where physical interventions (e.g. aerobic training, cycling to work) or mental interventions (e.g. stress resilience training, Yoga training) were investigated. The most commonly used markers for low grade inflammation was high sensitivity CRP, TNf-α and IL-6
Workplace physical exercise interventions were associated with a decrease in C-reactive protein (P<0.001). For other workplace interventions, i.e. .mental and organizational/structural, results were inconclusive.
The authors conclude that the research base is still limited, but the SR support that exercise interventions at or relate to the workplace might be able to reduce chronic low-grade inflammation.
A recent publication in NEJM identified a genetic background for a treatment-refractory and often fatal autoinflammatory syndrome developing in men with a mutation in UBA1 on the X chromosome, that codes for the major E1 enzyme initiating ubiquitylation. The clinical presentation includea adult-onset relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, giant-cell arteritis or a hematologic condition such as myelodysplastic syndrome or multiple myeloma. The disorder was named VEXAS, which relates to the vacuoles in myeloid and erythroid precursor cells, the E1 enzyme, X-linked phenotype, autoinflammatory presentation and the somatic mutation.
Beck et al.: Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
Fábio R. M. Leite
Inflammatory oral diseases share common causes with many systemic conditions, such as diabetes, metabolic disorders, and arthritis. In some cases, the initiation and exacerbation of oral tissues' destruction are observed even before detecting other clinical signs of such conditions. Dysfunctions in blood microcirculation and connective tissue metabolism are the most probable causes. Treatment for such conditions usually influences the progression of oral inflammatory diseases. The mouth may play a role in understanding the initiation and resolution of inflammation related to systemic conditions. These papers are based on one of our established cohorts, and they illustrate that systemic health and socioeconomic status play a significant role in developing inflammatory-driven destruction of the tissues around the teeth, known as periodontitis. To validate the close link between oral and systemic conditions, the authors demonstrate the size of the effect of interventions in common risk factors, such as obesity, alcohol, and smoking, in the prevention of oral inflammation.
Holger Jon Møller
Immunotherapy, a type of intervention that unleashes the body’s own immune cells to better fight cancer, has revolutionized the treatment of certain metastatic cancers such as advanced melanoma.
The focus for treatment has primarily been on adaptive immune checkpoints such as PD-1, but it doesn’t work for all. Researchers are therefore investigating options to improve current immunotherapy – e.g. by combined modulation of the innate immune defense to support the T-cell responses.
Another surprising option for increasing the efficacy of current immunotherapy was presented in Science in February 2021. In two small, uncontrolled trials, patients with PD-1-refractory melanoma showed improvement in response to anti-PD-1, if treatment was combined with a fecal microbiota transplant. This suggests that the microbiome may influence the tumor-micro environment and thereby increase the effect of immunotherapy.
The immune system has crucial homeostatic functions in adipose tissue. Inflammation of white adipose tissue is a hallmark of obesity. In a recently published study, Hildreth et al. by employing single-cell RNA-sequencing, report new subsets of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage that accumulate in obese white adipose tissue. This new perspective on the cellular landscape of adipose tissue provides novel insights into potential functions, regulation and interaction of known and newely identified immune cells clusters that residue in white adipose tissue. Furthermore, this study offers a valuable resource for further investigation regarding mechanisms and therapeutic targets that may help reduce inflammation in obese patients.
Karina Dalsgaard Sørensen
Checkpoint inhibitors (CPI) have revolutionized cancer treatment, leading to longterm survival for many patients who were previously left with very little hope. However, not all cancers respond to CPI and acquired resistance to CPI treatment is a considerable challenge. Hence, in order to select the right patient for the right CPI at the right time (personalized medicine), there is a need for better and more accurate biomarkers that can predict response to CPI and hence guide treatment selection.
Litchfield et al. used a “big data” approach to search for novel biomarkers of CPI response through a meta-analysis of whole-exome sequencing (WES) and transcriptomic (RNA sequencing) data from over 1000 CPI-treated patients across seven cancer types (urothelial cancer, malignant melanoma, head and neck cancer, non-small cell lung cancer, renal cell carcinom, colorectal cancer, and breast cancer).
The meta-analysis revealed that clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and bulk tumor CXCL9 gene expression. Copy number analyses also identified TRFA2 loss and CCND1 amplification in the tumor to be associated with CPI resistance across multiple cancer types. Finally, transcriptomic analyses of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs) identified CCR5 and CXCL13 as T-cell intrinsic markers of response to CPI.
Although further clinical validation is needed, the study provides important novel insights into the molecular and cellular mechanisms that control CPI response, including complex crosstalks between cancer cells and infiltrating immune cells in the tumor microenvironment.
Chronic kidney disease (CKD) affects approximately 10% of the adult population worldwide and is characterized by the development of renal injury and fibrosis and progressive loss of renal function, ultimately CKD leads to end-stage renal disease (ESRD). The incidence and prevalence of CKD has been increasing concurrently with the increase in lifestyle diseases such as diabetes, hypertension, obesity and longer lifespan.
It is now recognized that CKD is not always progressive, but that regression of albuminuria and improvement in renal function can occur if the injurious stimulus is removed. However, the cellular and molecular pathways mediating injury regression are poorly understood, partly because renal biopsies are rarely performed in patients who are clinically improving.
This paper shows that the innate immune system is central to injury and repair in the kidney and describe the heterogeneity of myeloid cell subsets behind these processes. Using complementary technologies, including bulk tissue transcriptomics, integrated droplet– and plate-based single-cell RNA sequencing, and paired blood exchange, the authors resolved myeloid cell heterogeneity in a murine model of reversible unilateral ureteral obstruction by creating a single-cell atlas.
Taken together this paper identifies novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
Søren Egedal Degn
Antibodies produced in response to infection or vaccination are a central component of our immune defense against infectious pathogens. However, they can also wreak havoc when erroneously targeted towards components of our own cells or tissues, as seen in a broad spectrum of autoimmune diseases. High quality antibodies are produced by B cells in induced microanatomical structures called germinal centers, within our secondary lymphoid tissues. In germinal centers, B cells undergo a Darwinian process of somatic hypermutation of their immunoglobulin genes followed by selection of variants with improved affinity for antigen. Over the course of the immune response, this drives the process of affinity maturation, which improves the specificity and affinity of antibodies produced. The length of the duration of this process determines, on one hand, the degree of affinity maturation towards the eliciting antigen, on the other, the risk of inadvertently generating novel potentially autoreactive specificities, due to the random nature of hypermutation. For this reason, the duration of the germinal center response has to be tightly controlled, but it has been unclear what determines this critical timing. Using intravital imaging of mouse germinal centers and single-cell RNA sequencing, Gabriel Victora’s group recently reported in Science, that termination of germinal centers coincides with upregulation of the transcription factor FoxP3 in T follicular helper cells. Surprisingly, these cells acquire a regulatory T cell–like phenotype, yet are distinct from T follicular regulatory cells, and are absolutely required to shut down the GC reaction. Tweaking this process may be key to extending germinal center lifetimes to enhance antibody responses in the context of vaccination, as well as controlling hyperactive and chronic germinal center responses associated with autoimmunity and chronic infections.
Immunological tolerance is a physiological mechanism of immense impact our health. Failure is associated with autoimmune disease, several of considerable burden to our health care system such as rheumatoid arthritis and multiple sclerosis. Available therapies are almost entirely acting on the symptoms by lowering inflammation. However, a new direction has been taken by David C. Wraith, whose work enabled clinical trials in restoring tolerance in multiple sclerosis patients. In the Paper of the Month, Schurgers and Wraith give a succinct review of state of the art and point to a new application of tolerance inducing therapies, namely to permit reconstitution with Factor VIII, a protein of the coagulation cascade. Undoubtedly, these directions will take immunotherapies into new territories.
Systemic inflammation measured by the acute-phase protein CRP associates with poor outcome across cancer types. In contrast, local tumor-associated inflammation, primarily evaluated by T-lymphocytes, correlates with favorable prognosis. Yet, little is known whether these two responses are related or opposing processes and why elevated CRP in relation to cancer is detrimental for clinical outcome. This article presents a platform combining multiplexed immunohistochemistry and digital imaging, enabling a virtual readout of both lymphoid and myeloid immune markers and their spatial patterns in the primary tumors of resected stage II and III colon cancer (CC) patients with and without accompanying systemic inflammation. The data in the article highlight the importance of a comprehensive immune classification of tumors including players of innate immunity and support a role for CRP as an informative biomarker of the immune response taking place at the tumor site.
Exposure to respirable crystalline silica is suggested to increase the risk of Inflammatory disease including rheumatic diseases. In this nationwide register-based study, Boudigaard et al examined the association between respirable crystalline silica and systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis. The authors included 1,541,505 male and 1,470,769 female workers followed since entering the labour market 1979–2015. Each worker was annually assigned a level of respirable crystalline silica exposure estimated with a quantitative job exposure matrix. 4673 male and 12 268 female cases were identified in the Danish patient register.
Boudigaard et al observed increasing risk of autoimmune rheumatic diseases following increasing occupational exposure to respirable crystalline silica, strongest for systemic sclerosis and rheumatoid arthritis, and most pronounced for men.
The paper by Ablasser and co-workers from Swiss Federal Institute of Technology Lausanne published in Nature, identifies a novel mechanism whereby SARS-CoV-2 induces mitochondrial DNA release, cell death and type I interferon (IFN) production in COVID-19 and further demonstrates that pharmacological inhibition of DNA sensing pathways alleviates pathology and may represent a therapeutic target.
Whereas type I IFN is essential for mounting antiviral responses early during SARS-CoV-2 infection, these same IFNs may be deleterious later during infection and contribute to inflammation, immunopathology, and tissue damage. In this work the authors investigated skin tissue from patients with dermatological manifestations of COVID-19, post mortem lung samples from patients with severe disease, as well as a mouse model. They identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a major mediator of aberrant type I IFN responses and pathology in COVID-19. Through immunological profiling of COVID-19 skin manifestations, they uncover a STING-dependent type I IFN signature primarily generated by macrophages residing in areas of endothelial cell damage. They further show that SARS-CoV-2 infection activates cGAS-STING signaling in endothelial cells through mitochondrial DNA release, resulting in cell death and excessive type I IFN production. This is complemented by data from a mouse model, in which pharmacological inhibition of STING reduces SARS-CoV-2-induced lung inflammation and improves disease outcome.
Collectively, this study establishes a mechanistic basis of pathological type I IFN production in COVID-19, by identifying the cytosolic cGAS-STING pathway as responsible for virus-induced mitochondrial DNA-mediated triggering of pathological type I IFN responses and tissue immunopathology, and finally demonstrate that pharmacological inhibition of this pathway reduces type I IFN and tissue pathology, thereby suggesting that the cGAS-STING pathway may represent a therapeutic target of potential clinical relevance.
Fabio Renato Manzolli Leite
The oral mucosa is a poorly studied barrier tissue with an important role in training immune tolerance due to large exposure to antigens of a stable commensal community. Periodontitis, a chronic inflammatory condition of the teeth supporting tissues associated with a microbial dysbiosis, is modified by multiple host response genes combined with lifestyle and environmental factors. Periodontal diseases share common inflammatory components with other chronic diseases, such as rheumatoid arthritis, inflammatory bowel disease, and diabetes. Some studies demonstrate that individuals susceptible to chronic inflammatory diseases present signs of periodontitis before the clinical systemic manifestations.
Little is known about why 10%-20% of the population develops a moderate to severe periodontitis and usually they are unresponsive to current therapies targeted at the microbial community. Leite et al. showed that some people from their very young adulthood have an exaggerated immune response to biofilm accumulation. These individuals showed a distinct profile of pro-and anti-inflammatory cytokine release. The two cytokine profiles were dubbed "non-organized response" with an aggregation of IL-4, IL-6, IL-8, IL-12, and IL-13 and "organized response" IL-2, IL-10, and TNF-α. Participants with fast development of inflammation presented a higher "non-organized response" factor and a lower "organized response" factor.
Williams et al. compiled a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. They describe the epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defences and neutrophil recruitment. They corroborate the exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis opening a new field of studies for oral and systemic manifestation of some inflammatory conditions.
Holger Jon Møller
Immunotherapy, a type of intervention that unleashes the body’s own immune cells to better fight cancer, has revolutionized the treatment of certain metastatic cancers such as advanced melanoma.
The focus for treatment has primarily been on adaptive immune checkpoints such as PD-1, but it doesn’t work for all. Researchers are therefore investigating options to improve current immunotherapy – e.g. by combined modulation of the innate immune defense (such as tumor associated macrophages) to support the T-cell responses.
Macrophage checkpoints - such as SIRPα that binds to CD47 on the tumor cells - are promising targets for increasing phagocytosis of tumor cells. However such therapy has hitherto been limited to a subset of patients
A new study in mice has now shown that combining CD47 targeted therapy with the well known chemotherapeutic Paclitaxel (Taxol) dramatically enhance the anti-cancer efficacy as compared to CD47 targeting alone.
This immunotherapeutic strategy may lead to a new paradigm of using Paclitaxel to activate TAMs and thereby in combination with macrophage immune checkpoint inhibitors, improve cancer treatment.
Karina Dalsgaard Sørensen
Cancer has long been perceived as a disease of the human genome. However, recent lines of evidence point to a more prominent role of the human microbiota in cancer development and progression. This novel insight has significant clinical implications for patient treatment and early detection of cancer. Nevertheless, the field of microbiome research in cancer is still in its infancy and its relevance to prostate carcinogenesis is far from being understood.
A recent study aimed to map the microbial composition within malignant and benign prostate tissue from patients suffering from prostate cancer, in the hope of finding associations between cancer development/progression and the composition of the prostate tissue microbiome. The authors identified several microbial species to be in dysbiosis within malignant compared to benign prostate tissue. Microbial dysbiosis was also associated with altered immune regulation within the prostate tissue.
These findings point to the future possibility of using certain microbial species as diagnostic/prognostic biomarkers in prostate cancer, or even as novel treatment targets for achieving better response. Immunomodulatory effects of certain species could also be targets for future immunotherapy.
Salachan et al.: Microbiota of the prostate tumor environment investigated by whole-transcriptome profiling
Joanna Maria Kalucka
Breast cancer (BC) is the most frequently diagnosed cancer in women in the US and Europe. Despite improvements in anti-tumour therapy, BC remains the second leading cause of cancer deaths in women. Metastatic relapse is the leading cause of this high mortality and occurs for long periods after removing the primary tumour. Therefore, understanding the mechanisms that control metastasis is pivotal for designing an improved and safe BC treatment regimen.
Changes in cell metabolism have been shown to be essential for several steps of metastasis: metabolism can support tumour growth and facilitate cancer-cell survival in the bloodstream and help to disseminate to distant organs. However, so far, no one has addressed whether a cellular metabolism can influence cancer cell abilities to m
In a recent study published in Nature, by Rossi et al., investigated the role of the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH), which is known to be overexpressed and/or amplified in 70% of triple-negative breast cancers (TNBC). The authors report that intra-tumour heterogeneity and low expression of PHGDH protein in primary TNBC correlate with poor metastasis-free survival in patients. Strikingly loss of PHGDH in mice promotes cancer cell dissemination and metastasis formation. Furthermore, the changes in PHGDH expression associated with metastatic stage of cancer cells, for example, early metastatic lesions and circulating cancer cells, show low or no PHGDH expression, while advanced proliferating metastases express PHGDH. Furthermore, the downstream analysis revealed that cancer cells lacking PHGDH enzyme had higher expression of genes associated with cell migration, invasion and transformation. The authors also reported that cells with low PHGDH expression showed more migratory capacity than those with high PHGDH from the same tumour. These results elegantly link metabolic heterogeneity with gene-expression programs related to tumour metastasis, and these findings showcased that low enzyme levels are sufficient to induce aggressive features in cancer cells.
Mechanistically, PHGDH altered cell migration by directly binding to another metabolic enzyme: phosphofructokinase (PFK), a key glycolytic pathway component. Upon loss of PHGDH, the activity of PFK decreases which redirects the carbon flux into another metabolic pathway: the hexosamine-sialic acid pathway. Consequently, glycosylation (sialylation) of integrin alpha-v-beta-3, a key component for cell migration, is increased, which inhibits the invasiveness of PHGDH low cancer cells and metastasis formation.
Intriguingly, the authors report that cancer cells with low levels of the PHGDH tended to locate near vascular tissue. This implies that endothelial cells can modulate PHGDH expression and thus have an effect on cancer cell invasiveness. Even though the factors and the insights on this mechanisms still have to be defined, this study highlights a possibility of signalling from endothelial cells that directly affects the expression of a metabolic enzyme in tumour cells.
Taken together, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. This study broadens our understanding of the role of metabolic heterogeneity in cancer and might point toward new approaches for targeting diverse tumour-cell populations in order to suppress tumor metastases.
Rossi, M. et al.: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis https://www.nature.com/articles/s41586-022-04758-2
Acute kidney injury (AKI) is defined by an abrupt decrease in renal function. The incidence of AKI varies from 5% in all hospitalized patients to 30-50% in intensive care units. Most interventional trails in AKI have failed in humans so there is a need for better therapeutic approaches to prevent or treat AKI.
There is an increasing evidence for an important role for the innate immune cells in propagation of AKI. Following acute injury to the kidney, macrophages plan an important role in recovery of functional and structural integrity, but renal fibrosis and progressive functional decline occur with incomplete recovery
This paper described a novel mechanism by which prostaglandins modulate macrophage phenotype following AKI and provide new insight into mechanisms underlying detrimental kidney effects of non-steroidal anti-inflammatory (NSAID) drugs that inhibit cyclooxygenase activity.
Søren Egedal Degn
The production of highly specific antibodies is one of the most striking features of our immune response to infectious microorganisms. The presence of such antibodies can provide long-lived protection against the eliciting pathogen (sometimes life-long!), a feature which we also harness through vaccination. The first step in activation of this antibody response is the engagement of the B cell receptor (BCR) by antigen. Surprisingly, to this day, there is no broad consensus on how this engagement triggers activation of the BCR. Despite the pervasive text-book description of a mechanism of activation driven by ‘clustering’, this model is not supported by data, and numerous competing modes of activation have been proposed in the field. The BCR is in essence a membrane-bound version of the respective antibody produced by a given B cell, with the important addition of a transmembrane domain and direct association with essential signaling components called CD79a and CD79b (or Iga and Igb, respectively). Although the structure of antibodies has been known for well over 50 years, since Gerald M. Edelman and Rodney R. Porter’s Nobel Prize winning work, the elucidation of the precise mechanism of antigen triggering of the BCR has been severely hampered by the paucity of structural information on the precise configuration and conformation of the receptor.
This past month, two back-to-back Science papers blasted through this impasse using Cryo-electron microscopy (Cryo-EM), a relatively new weapon in the arsenal of structural biologists, which allows the resolution of previously unattainable targets. The structures presented provide important new insights about the organization of the transmembrane domain of the BCR and its interaction with CD79. However, as they only present the resting (non-antigen-engaged) configuration of the complex, they do fall short of providing the smoking gun evidence for any of the proposed mechanisms of activation. Nonetheless, the success of this ‘impossible’ step holds the promise to provide the final evidence shortly down the road, as the antigen-engaged conformation will undoubtedly soon be revealed!
Xinyu Ma et al.: Cryo-EM structures of two human B cell receptor isotypes | Science
Qiang Su et al.: Cryo-EM structure of the human IgM B cell receptor | Science
Related perspective: Unveiling the B cell receptor structure | Science
The laboratory of Prof. Simon J. Davis, University of Oxford (Davis Lab Oxford), has focused on describing the function co-stimulatory molecules in the cell membrane of especially T cells. Among many important contributions, the so-called kinetic segregation (ks) model describes T cell signaling because of intramembrane reorganization of receptors with an intracellular part containing either kinases or phosphatases. A net signaling occurs when large phosphatase-containing molecules such as CD45 are denied access to the smaller, kinase-containing CD3. This happens when the immunological synapse is formed where simple geometry forces larger molecules out of the contact zone between an antigen-presenting cell and the T cell. In their recent paper, Sušac et al. now investigates the role of conformational change in the T cell receptor as part of the signaling. From high-resolution structures, they show that such signaling can occur without conformational change. As concluded in the study, the data are consistent with the notion that a T cell receptor ligand may need only to bind the receptor, holding the TCR in regions of the membrane that favor signaling in accordance with the ks model.